ERBB2 Amplification and HER2 Expression in Salivary Duct Carcinoma: Evaluation of Scoring Guidelines and Potential for Expanded Anti-HER2 Therapy.

Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.

HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy.

Among gynecologic cancers, uterine serous carcinoma (USC) has been shown to be human epidermal growth factor receptor 2 (HER2) amplified and trastuzumab has been included in the recent National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced stage or recurrent USC with HER2 overexpression/amplification. There is limited literature suggesting that a subset of high-grade endometrioid carcinomas with aberrant p53 expression may also be HER2 amplified and these patients could benefit from the addition of targeted therapy. We identified 59 p53-aberrant (mismatch repair proficient) FIGO 3 endometrioid carcinomas of the uterus. HER2 immunohistochemistry was performed in all 59 tumors and HER2 fluorescence in situ hybridization (FISH) was performed in 52 of the 59 cases. Four of the 59 cases were HER2 3+ by immunohistochemistry (6.7%), using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2007, 2013, and 2018 criteria. HER2 FISH was performed in 3 of the 4 cases and was amplified in all 3. Nine, 8, and 7 tumors showed 2+ HER2 staining when applying 2018, 2013, and 2007 criteria, respectively, FISH was performed in 7 tumors and none were amplified. An additional 4 cases did not perfectly meet the 2018 ASCO/CAP criteria but were assigned a score of 2+, none were amplified by HER2 FISH. The remaining 42 cases showed 1+ or no staining for HER2, FISH was successfully performed in 38 tumors and none showed amplification. Approximately half of the tumors fulfilled criteria for HER2-low or HER2-very low (10 HER2-low and 20 HER2-very low). Our data shows that a subset of p53-aberrant high-grade endometrial endometrioid carcinoma express HER2 and these patients may benefit from the addition of targeted therapy. The role of targeted therapy in HER2-low gynecologic carcinoma is currently unexplored.

Clinical and Pathologic Features Associated With Invasive Breast Carcinoma With 2018 American Society of Clinical Oncology/College of American Pathologists In Situ Hybridization Group 2 Results (Human Epidermal Growth Factor Receptor 2 [HER2]/Chromosome 17 Centromere [CEP17] Ratio ≥2.0 and Average HER2 Copy Number <4.0).

CONTEXT.­: The American Society of Clinical Oncology/College of American Pathologists updated the human epidermal growth factor receptor 2 (HER2) breast carcinoma testing guideline in 2018 to address issues from uncommon HER2 fluorescence in situ hybridization (FISH) results. Based on the 2013 American Society of Clinical Oncology/College of American Pathologists guideline, cases wherein the HER2/chromosome 17 centromere (CEP17) ratio of 2.0 or more with an average HER2 copy number of less than 4.0 were considered in situ hybridization (ISH) positive. Under the 2018 guideline, such cases are classified as ISH Group 2 and are no longer considered eligible for anti-HER2 therapy when the corresponding HER2 immunohistochemistry result is 0, 1+, or 2+. OBJECTIVE.­: To assess the clinical, pathologic, and treatment aspects of patients with ISH Group 2 results. DESIGN.­: We retrospectively reviewed HER2 FISH results at our center between January 2012 and December 2014 and identified and characterized cases with ISH Group 2 results. RESULTS.­: Thirty-nine cases with ISH Group 2 results from 39 patients were reviewed. Twenty of 39 (51%) patients received anti-HER2 therapy. Patients treated with HER2-targeted therapy were less likely to have hormone receptor-positive tumors, compared with patients without anti-HER2 treatment, though not significantly (P = .30). The only significant difference between the 2 patient groups was receipt of cytotoxic chemotherapy treatment (P < .001). Overall, clinical outcome was similar between the 2 groups (P > .99). CONCLUSIONS.­: This retrospective study with median follow-up of at least 6 years shows patients with ISH Group 2 tumors had similar clinical outcomes, irrespective of HER2-targeted therapy. Further analysis in the prospective setting would provide valuable data that would potentially inform clinical decision making.